A prospective cohort study on longitudinal trajectories of cognitive function after stroke

The study aimed to determine longitudinal trajectories of cognitive function during the first year after stroke. The Montreal Cognitive Assessment (MoCA) was used to screen cognitive function at 36–48 h, 3-months, and 12-months post-stroke. Individuals who shared similar trajectories were classified by applying the group-based trajectory models. Data from 94 patients were included in the analysis. Three cognitive functioning groups were identified by the trajectory models: high [14 patients (15%)], medium [58 (62%)] and low [22 (23%)]. For the high and medium groups, cognitive function improved at 12 months, but this did not occur in the low group. After age, sex and education matching to the normative MoCA from the Swedish population, 52 patients (55%) were found to be cognitively impaired at baseline, and few patients had recovered at 12 months. The impact on memory differs between cognitive functioning groups, whereas the impact on activities of daily living was not different. Patients with the poorest cognitive function did not improve at one-year poststroke and were prone to severe memory problems. These findings may help to increase focus on long-term rehabilitation plans for those patients, and more accurately assess their needs and difficulties experienced in daily living.

Clinical assessments. The MoCA was administrated to evaluate cognitive functioning at an interval of 36 to 48 h after stroke (referred to as baseline), 3-months and 12-months after stroke. The MoCA is a valid and reliable instrument for screening of global cognition in patients with mild to moderate stroke 17,18 . The MoCA consists of subdomains following visuospatial/executive, naming, attention, abstraction, delayed recall or memory and orientation. A maximum score is 30, where lower indicates worse cognition 19 . One extra point was added to the final score if patients had less than or equal to 12 years of education. Written permission for using the MoCA test was obtained from MoCA© (MoCA-Cognitive Assessment https:// www. mocat est. org).
Neurological deficits were evaluated using NIHSS at Day 2 after admission 20 . Motor-sensory function in the extremities was tested using the Fugl-Meyer Assessment Scale (FMA; lower extremity [-LE] and upper extremity [-UE]), with a lower FMA score indicating a more severe impairment of function 21 . Clinical measurements were conducted by an experienced physiotherapist and/or occupational therapist.
Self-assessed measures. Psychological distress was assessed using the 14-item Hospital Anxiety and Depression Scale (HADS) self-assessment questionnaire, which comprised a 7-item subscale to assess anxiety and a 7-item subscale to assess depression 22 . Each item consists of four response levels, scored from 0 to 3. Mild and moderate anxiety or depression is attributed to a score above 7 points on the subscale 22 .
Memory performance and activities of daily living, two major domains which impact health-related quality of life after stroke, were assessed using the Stroke Impact Scale (SIS, version 3.0) 23 . The SIS is a 59-item multidimensional self-assessed measure of eight domains: strength, memory and thinking, emotion, communication, activities of daily living, mobility, hand function, and participation. Each domain contains a various number of items and each item has five response level to score their self-perceived difficulties after stroke. Memory (8 items) and ADL/IADL (10 items) of SIS-subdomains were used in this study to determine the impact of cognitive function in patients after stroke. Written permission of using the SIS scale version 3.0 was granted in 2006 from MAPI Research Trust, Lyon, France (https:// www. mapi-trust. org). All the self-reported assessments were administered on Day 5 to not overburden the patients.

Statistical analysis. Longitudinal trajectories of cognition.
Cognition assessed by MoCA was transformed through converting each individual's MoCA score into proportions, by dividing by the maximal MoCA score (30 points). The proportional MoCA scores are continuous with an interval from 0 to 1, and an upper and lower limited bound of 0.005 and 0.995 were used, respectively, to fit a beta distribution. Patients were considered lost to follow-up if there were more than two missed visits and were further excluded from the longitudinal analysis.
The longitudinal changes in cognition of the study sample were analyzed using a longitudinal beta regression mixed-effect model, while adjusting for age and sex 24 . Age was dichotomized to < 75 and ≥ 75 years using the median value. Time, age and sex were included as fixed effect, and random intercept was also used. Akaike information criterion, Bayesian information criterion, and pseudo-R 2 were used to evaluate the model performance.
A group-based trajectory model was used for clustering, which is a finite mixture modelling designed to classify individuals who share similar longitudinal trajectories into clusters by fitting the developmental course of each individual over time using maximum likelihood estimation 25,26 . Group-based trajectory models specified for beta distribution were applied in this study to identify the subgroups that followed similar progression of cognition over time after stroke 27 . The subgroups were stratified through the highest predicted probability assigned to individuals. Model evaluation and selection for developmental trajectories was based on the Bayesian information criterion and average posterior probability.
Cognitive impairments. By identifying patients with cognitive impairments, normative data on MoCA from the Swedish general population was used as a reference by matching age, sex and education 28 . Cognitive impairment was defined by whether the individuals' total MoCA score was larger than or equal to 1 standard deviation of normative cognition after age-, sex-, and education-matching, after removal of an extra point for low education 28 . The number of patients with cognitive impairments in different trajectory groups was explored across the three time points.

Impact of longitudinal cognition on activities of daily living and memory. Both memory and
ADL/IADL domains of SIS were transformed to a continuous index, ranging from 0 to 100 (a lower score indi-  29 . The means scores for SIS-memory performance and SIS-ADL/IADL were compared between different trajectory groups, as well as between different time points. For group comparison, either Fisher's exact test, Pearson's χ 2 test, Mann-Whitney U test, independent t tests, Kruskal-Wallis test, and 1-way analysis of variance was used, as appropriate. To compare changes between different time points in SIS and the subdomains of MoCA, either Friedman Test, repeated-measures analysis of variance, paired t test or Wilcoxon signed-rank was used, as appropriate. Significance for multiple comparisons was adjusted using Holm-Bonferroni corrections. A two tailed significance level was defined as p < 0.05. The effect size was also calculated for each applied statistical test to determine the magnitude of difference. Statistical analyses were performed using SAS (SAS Institute Inc., Cary, NC, USA) and IBM SPSS statistics 25 (IBM Corp., Armonk, NY).

Results
One hundred and forty patients were eligible for the study trial and five patients withdrew prior to the baseline assessments. Details of inclusion and exclusion in the longitudinal data analysis are presented in a flow chart (Fig. 1). No statistically significant difference was found between the patients excluded and those included in the study in terms of age, sex and neurological deficits. Data from 94 patients were included in the longitudinal analysis [median age 76 years, range 37-96, 40 females (43%); Table 1].  Table 1. Cluster I was characterised by high cognitive functioning, with the highest mean MoCA scores across the three time points. Cluster II was termed the medium cognitive functioning group, and had overall mean MoCA scores lower than cluster I, but higher than cluster III. The low cognitive functioning www.nature.com/scientificreports/ group (defined as cluster III) showed the lowest mean MoCA scores. There were significant differences between the three trajectory groups in total MoCA scores at baseline, 3-months, and 12-months post-stroke (Table 1). For longitudinal changes in cognitive scores for each group, the high and medium cognitive functioning group showed significant improvements from baseline to 12 months (improved 2 median MoCA scores; p = 0.02, effect size Kendall's W [W] = 0.32 for the high group; and p = 0.002, W = 0.17 for the medium group, Table 1). From baseline to 3-months, only the medium group showed significantly improved cognitive function (improved 1 median MoCA score, adjusted p = 0.002, effect size r = 0.54). No significant changes in cognition neither from baseline to 3 months, nor from 3-to 12-months post-stroke, were noted for the other two groups. Individual changes in cognitive functioning over time by the cognitive functioning groups are shown in Fig. 2.

Longitudinal trajectories of cognitive function during the first year after stroke.
The mean scores of MoCA subdomains by cognitive functioning groups over time are shown in Fig. 3. Most subdomains of MoCA showed statistically significant differences between cognitive functioning groups, except for the subdomain of naming at baseline.    Among the cognitive functioning groups, there were significant differences in the number of patients with cognitive impairments at baseline, 3-months, and 12-months post-stroke (adjusted p < 0.001). The percentage of patients with cognitive impairments across the three time points in each group is presented in Fig. 1.

Impact on memory performance and activities of daily living in different cognitive functioning groups.
Among the cognitive functioning groups, there were significant differences between groups in memory performance, assessed by SIS, at baseline (adjusted p = 0.006, effect size E 2 R = 0.14), 3-months (adjusted p = 0.003, E 2 R = 0.18), and 12-months post-stroke (adjusted p = 0.01, E 2 R = 0.13, Fig. 4). No significant differences between groups were found at any time points in the ADL/IADL domain assessed by SIS.
There was a significant change for the medium group in memory performance from baseline to 12-months post-stroke (mean difference = − 2.8, p = 0.01, W = 0.09). For the impact on ADL/IDL over time between groups, significant improvements were seen both for the medium and high group from baseline to 12-months post-stroke (mean difference = 14.6, p = 0.009, W = 0.36 for the high group; mean difference = 17.3, p < 0.001, W = 0.5 for the medium group). There were no significant improvements in SIS-ADL/IADL noted in the low group.

Discussion
This longitudinal study demonstrated that the trajectories of cognition in stroke patients improved during the first three months, but subsequently remained unchanged until 12 months, after stroke. The group based-trajectory model stratified three levels of cognitive functioning: low, medium and high. After being age, sex, and educationmatched with normative MoCA of the Swedish population, half of the study sample (55%) was found to have cognitive impairment at baseline, and 25% of these patients recovered after 12 months. The impact on memory performance significantly differed between cognitive functioning groups, whereas the impact of ALD/IADL was not different between groups.
Consistent with the general pattern of stroke recovery 30 , improvements in cognition were found solely within the first three months and tended to decline after that for the low cognitive functioning group in the present study. The improved cognition for the medium and high cognitive functioning groups was higher than the minimal clinically important difference of MoCA which with an estimate of 1.22 was previously suggested 31 . However, there were diverse patterns for changes in cognition shown after 3-months post-stroke or a longer time of follow-up, depending on the cognitive instruments used 10 . This may imply that the evolution of cognition is rather heterogenous and the rate of recovery differs significantly among stroke patients. The study findings based on the trajectory-model could contribute to deciphering heterogeneity by stratifying patients with similar developmental patterns over the course of time and identifying potential subgroups that may likely be susceptible to cognitive decline or poor recovery.
Patients with the poorest cognitive function, whose cognition did not improve during the first year after stroke, were older and had more frequent depressive symptom. This is in line with factors responsible for cognitive decline from earlier findings 11,12 . Furthermore, more severe initial cognitive impairment may reflect a decrease in neurological reserve and neuroplastic potential, which might lead to a poor recovery 32,33 . The low www.nature.com/scientificreports/ cognitive functioning group showed a substantially poor performance in the memory/delay recall domain over time and a significant decrease in language performance at 12-months post-stroke. The association between deficit of language expression and a greater risk of progressive cognitive decline was shown in a previous study 34 .
Language deficits in stroke patients commonly involves left-side lesions, but this cannot be determined in our study sample due to the small sample size. However, various findings of the hemisphere of the lesion as a predictor for stroke recovery have previously been reported [35][36][37] .
Half of the study sample exhibited cognitive impairment at baseline. The prevalence in our study sample was similar in comparison with other studies that demonstrated a range from 30 to 74% depending on instruments used 3,4,38 . The patients who recovered at 12-months post-stroke were from the medium or high group, and none of the patients with cognitive impairment in the low group recovered. This further suggests that the patients with baseline severe cognitive deficits may show difficulty in recovering over time after stroke, and the loss of cognition may not be reversible.
Patients with lower cognitive functioning perceived a large impact on their memory performance as well as activities of daily living, compared to those with higher cognitive function. Perceived difficulties in these two SIS domains have been frequently reported in patients with cognitive impairment 39 . However, the perceived impact on memory performance did not change during the first year after stroke, and although there was a slight decrease in the mean score of the medium group, the effect size was considered to be very small. This could be due to a lack of awareness of cognitive problems. In contrast, the impact on activities of daily living was noted to be clinically meaningful, with changes from the baseline to 12-months post-stroke for the medium and the high group, as a clinically important difference of 5.9 was suggested 40 . The underlying reason maybe that the improved cognition has a positive impact on their activities of daily living, as was also previously shown 41 . Furthermore, as there was no group difference in ADL/IADL across any time points, this finding suggested that the patients with the poorest cognitive functioning may have difficulty to perceive their daily problems. This highlights the importance of recognising these patients early at baseline and the need to appropriately assess their potential difficulties along with a long-term follow-up plan.
The strength of the study is that the cognitive function assessed by MoCA was conducted in the very early stages of stroke and patients were followed up to 1 year. This captures a relatively complete picture of dynamic changes of cognition from the acute to chronic phase. The advance in the group-based trajectory model was able to identify patients with similar progress patterns, while deciphering certain heterogeneity from the disease group. Moreover, cognitive impairment was defined by age, sex and education-matching with the Swedish general population, which provides a more appropriate assessment of cognitive impairment in comparison to the use of a single cut-off of MoCA.
There were limitations that need to be addressed in this study. As one of the limitations, the included patients, in general, had mild to moderate neurological deficits; therefore, the cognitive function may be overestimated and thus have limited generalisability. However, it needs to be emphasised that a high score in ADL assessment does not necessarily suggest that patients do not suffer from cognitive impairment. With a mild cognitive impairment, patients may be able to perform basic activities of daily living, but there may be a more substantial impact on more complex activities that involve planning and executive function. This may explain why no group difference was found in SIS-ADL/IADL at any time point, as this domain was dominated by basic activities of living items. In addition, patients with severe cognitive deficits may have difficulties in realizing their limitations with basic ADL. The study findings may facilitate the improvement of recognition of cognitive impairments in those patients who score well in ADL assessments.
One more limitation is that the effect of some factors (such as localisation and initial clinical symptoms) on cognitive decline were not possible to explore due to the small sample size. Although substantial effort has been made to assess neuroimaging findings, precise lesions and volume were difficult to determine and were not within the scope of the study. This study has a primary interest in longitudinal trajectories in cognition assessed using MoCA. Furthermore, data on pre-morbid cognition as well as comorbidities were not available, and is also considered as one of the limitations. Including these variables into analyses, might offer a better understanding on longitudinal trajectories of cognition after stroke. The MoCA has similar limitations as in other cognitive instruments; for example, the ceiling effects on MoCA may be limited in its ability to detect potential improvement in the high cognitive functioning group 42 . The MoCA as a global measure of cognition may not capture subtle cognitive changes. There is a need for assessing executive function and subjective cognitive complaints, and tools for that are desirable. Also, the MoCA assessments could not be conducted for patients with aphasia or hemiplegia, which could result in an overestimation of the functioning. However, MoCA has previously been shown to be a feasible and sensitive tool for use in a very early stage of stroke to screen cognitive function and with excellent accuracy for detecting cognitive impairments among the available cognitive instruments 17,18 .

Conclusion
Cognition after stroke, in general, improved during the first three months, but no significant improvement was found at any time point for patients with the poorest cognitive function who were older, more frequently suffering from depression, and prone to severe memory problems. This study may help to focus on rehabilitation plans for those patients and to more accurately assess their needs and difficulties in daily living.